A comparative analysis is provided of rigorous and approximate methods for calculating absolute binding affinities of two protein-ligand complexes: the FKBP protein bound with small molecules 4-hydroxy-2-butanone and FK506. Our rigorous approach is an umbrella sampling technique where a potential of mean force is determined by pulling the ligand out of the protein active site over several simulation windows. The results of this approach agree well with experimentally observed binding affinities. Also assessed is a commonly used approximate endpoint approach, which separately estimates enthalpy, solvation free energy, and entropy. We show that this endpoint approach has numerous variations, all of which are prone to critical shortcomings. For example, conventional harmonic and quasiharmonic entropy estimation procedures produce disparate results for the relatively simple protein-ligand systems studied in this work.
Abstract:We present a new hybrid explicit/implicit solvent method for dynamics simulations of macromolecular systems. The method models explicitly the hydration of the solute by either a layer or sphere of water molecules, and the generalized Born (GB) theory is used to treat the bulk continuum solvent outside the explicit simulation volume. To reduce the computational cost, we implemented a multigrid method for evaluating the pairwise electrostatic and GB terms. It is shown that for typical ion and protein simulations our method achieves similar equilibrium and dynamical observables as the conventional particle mesh Ewald (PME) method. Simulation timings are reported, which indicate that the hybrid method is much faster than PME, primarily due to a significant reduction in the number of explicit water molecules required to model hydration effects.
Combined-value auctions (CVAs) allow participants to make an offer of a single amount for a collection of items. These auctions provide value to both buyers and sellers of goods or services in a number of environments, but they have rarely been implemented, perhaps because of lack of knowledge and experience. Sears Logistics Services (SLS) is the first procurer of trucking services to use a CVA to reduce its costs. In 1993, it saved 13 percent over past procurement practices. Experimental economics played a crucial role in the development, sale, and use of the CVA.
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